The clinical usefulness of adriamycin is limited by its propensity to produce a severe, and sometimes fatal, cardiotoxicity. The mechanism of this toxicity has been ascribed to free radical formation, membrane perturbation, altered energy metabolism and interactions with vasoactive amines. Investigations into the actual mechanism(s) of adriamycin induced cardiotoxicity, however, have been hampered by the lack of an appropriate and universally accepted model system. Recently, we have been evaluating the fetal mouse heart organ culture as a new model to study direct effects of anthracyclines on cardiac tissue and as a method to rapidly screen large numbers of anthracyclines for cardiotoxic potential. To date, we have found the organ culture system to be a sensitive and selective indicator of adriamycin cardiotoxicity. Using the studies described in the present proposal, we intend to confirm the applicability of this model system to investigate adriamycin cardiomyopathy. To accomplish this goal, we have developed a research plan consisting of three distinct but interrelated phases. Phase I: The goal of phase I is to confirm the usefulness of the fetal mouse heart organ culture system as an effective in vitro screen to determine the relative cardiotoxicity of anthracyclines and anthraquinones rapidly and inexpensively. Phase II: The goal of phase II is to determine the biochemical, histologic, physiologic, and pharmacologic responses of the fetal mouse heart to anthracycline treatment. We intend to determine not only the degree of change induced by the anthracycline but also the dynamics of these changes since the understanding of both parameters is essential for identifying "key" lesions induced by anthracycline. Phase III: The goal of Phase III is to determine the effect of putative myocardial protectants on the anthracycline induced changes on the fetal mouse heart. We intend to use specific protectants, i.e. vitamin E (an inhibitor of lipid peroxidation), coenzyme QID (a cofactor required for appropriate energy production) and ICRF-187 (an iron chelator with demonstrated myocardial protection).